The Emory Alzheimer's Disease Research Center (ADRC) provides Georgia and the region with comprehensive clinical, research, and educational programs. This renewal application outlines our success in building an environment that encourages and supports innovative projects with a general theme of discovery and translation of new targets and mechanisms to enable early identification, early interventions, and ultimately prevention of AD. Given the well documented disparities in clinical research participation and burden of disease for AD in the African American community, the Emory ADRC focuses special effort to understand and address inter-individual differences in AD, ranging from ethno-racial factors to personal differences in genetic and protein variation. We benefit from generous institutional support from Emory, one of the nation's fastest growing research academic medical centers, the generous Atlanta community, and a highly collaborative team from more than 20 departments and centers. Five Cores (Administrative, Clinical, Data Management and Statistics, Neuropathology, and Outreach Recruitment and Education), coordinate activities to effectively recruit, evaluate, and engage a diverse cohort of volunteers who actively participate in a wide variety of research studies that aim to better define the trajectory from normal cognitive aging to symptomatic stages of disease. Data from the Cores are captured and stored for distribution to local researchers and for national collaborations. Our biospecimen banks include well-characterized neuropathological case materials, blood and CSF, and DNA. These valuable resources are distributed widely for a variety of approved studies of genetic, molecular, pharmacological, and pathological investigations. The ADRC educational programs reach a broad audience of students, health care professionals, and the public. Three cutting edge research projects are closely integrated with ADRC Cores: Project 1, AD Biomarkers and Endothelial Dysfunction in Caucasians and African Americans, is a longitudinal biomarker study with full integration into the ADRC Clinical Core and OREC, leveraging a unique community based Registry for Remembrance to facilitate recruitment of African Americans; Project 2, A Proteogenomic Approach to Understanding AD GWAS Results, proposes to use state-of-the art targeted gene resequencing and mass spectrometer-based protein sequencing to advance understanding of genetic risk of AD by genetic loci by linking novel gene variants at 20+ recently identified loci directly with the encoded and expressed protein variants in AD brain in an allele specific manner; Project 3, Defining the Properties of Pathogenic A? strains in Alzheimer's Disease, takes an interdisciplinary approach to build on pioneering work showing AD brain extracts are transmissible in animal models, by investigating how structural differences in A? strains from asymptomatic vs. symptomatic stages of AD vary in their seeding and propagation in yeast and animal models.